Tryptophan Challenge in Individuals with Schizophrenia and Healthy Controls: Acute Effects on Circulating Kynurenine and Kynurenic Acid, Cognition and Cerebral Blood Flow

Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975).